4-aryl-1-oxa-9-thia-cyclopenta[b]fluorenes

ABSTRACT

This invention provides compounds of Formula I having the structure ##STR1## wherein B and D are each, independently, hydrogen, halogen, --CN, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms; 
     R 1  is hydrogen, alkyl of 1-6 carbon atoms, --CH(R 2 )W, --C(CH 3 ) 2  CO 2  R 3 , 5-thiazolidine-2,4-dione, --CH(R 4 )CH 2  CO 2  R 3 , --COR 3 , or --PO 3  (R 3 ) 2  ; 
     R 2  is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, --CH 2  (1H-imidazol-4-yl), --CH 2  (3-1H-indolyl), --CH 2  CH 2  (1,3-dioxo-1,3-dihydro-isoindol-2-yl), --CH 2  CH 2  (1-oxo-1,3-dihydro-isoindol-2-yl), or --CH 2  (3-pyridyl); 
     W is --CO 2  R 3 , --CONH 2 , --CONHOH, --CN, CONH(CH 2 ) 2  CN, 5-tetrazole, or --PO 3  (R 3 ) 2  ; 
     R 3  is hydrogen, alkyl of 1-6 carbon atoms, or aryl; 
     R 4  is hydrogen or alkyl of 1-6 carbon atoms; 
     or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

This application claims the benefit of U.S. Provisional Application No.60/135,096 filed May 12, 1998, which was converted from U.S. patentapplication Ser. No. 09/076,623, filed May 12, 1998, pursuant to apetition filed under 37 C.F.R. 1.53(c)(2)(i) on Jul. 6, 1998.

BACKGROUND OF THE INVENTION

The prevalence of insulin resistance in glucose intolerant subjects haslong been recognized. Reaven et al (American Journal of Medicine 1976,60, 80) used a continuous infusion of glucose and insulin(insulin/glucose clamp technique) and oral glucose tolerance tests todemonstrate that insulin resistance existed in a diverse group ofnonobese, nonketotic subjects. These subjects ranged from borderlineglucose tolerant to overt, fasting hyperglycemia. The diabetic groups inthese studies included both insulin dependent (IDDM) and noninsulindependent (NIDDM) subjects.

Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which can be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia can be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

The association of hyperinsulinemia with obesity and with ischemicdiseases of the large blood vessels (e.g. atherosclerosis) has been wellestablished by numerous experimental, clinical and epidemiologicalstudies (summarized by Stout, Metabolism 1985, 34, 7, and in more detailby Pyorala et al, Diabetes/Metabolism Reviews 1987, 3, 463).Statistically significant plasma insulin elevations at 1 and 2 hoursafter oral glucose load correlates with an increased risk of coronaryheart disease.

Since most of these studies actually excluded diabetic subjects, datarelating the risk of atherosclerotic diseases to the diabetic conditionare not as numerous, but point in the same direction as for nondiabeticsubjects (Pyorala et al). However, the incidence of atheroscleroticdiseases in morbidity and mortality statistics in the diabeticpopulation exceeds that of the nondiabetic population (Pyorala et al;Jarrett Diabetes/Metabolism Reviews 1989,5, 547; Harris et al, Mortalityfrom diabetes, in Diabetes in America 1985).

The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it has been demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of the obese, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumreabsorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

It is now appreciated that insulin resistance is usually the result of adefect in the insulin receptor signaling system, at a site post bindingof insulin to the receptor. Accumulated scientific evidencedemonstrating insulin resistance in the major tissues which respond toinsulin (muscle, liver, adipose), strongly suggests that a defect ininsulin signal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (reviewed by Haring, Diabetalogia 1991, 34, 848).

Protein-tyrosine phosphatases (PTPases) play an important role in theregulation of phosphorylation of proteins. The interaction of insulinwith its receptor leads to phosphorylation of certain tyrosine moleculeswithin the receptor protein, thus activating the receptor kinase.PTPases dephosphorylate the activated insulin receptor, attenuating thetyrosine kinase activity. PTPases can also modulate post-receptorsignaling by catalyzing the dephosphorylation of cellular substrates ofthe insulin receptor kinase. The enzymes that appear most likely toclosely associate with the insulin receptor and therefore, most likelyto regulate the insulin receptor kinase activity, include PTP1B, LAR,PTPα and SH-PTP2 (B. J. Goldstein, J. Cellular Biochemistry 1992, 48,33; B. J. Goldstein, Receptor 1993, 3, 1-15,; F. Ahmad and B. J.Goldstein Biochim. Biophys Acta 1995, 1248, 57-69).

McGuire et al. (Diabetes 1991, 40, 939), demonstrated that nondiabeticglucose intolerant subjects possessed significantly elevated levels ofPTPase activity in muscle tissue vs. normal subjects, and that insulininfusion failed to suppress PTPase activity as it did in insulinsensitive subjects.

Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTPase activity in the livers of two rodentmodels of IDDM, the genetically diabetic BB rat, and the STZ-induceddiabetic rat. Sredy et al (Metabolism, 44, 1074, 1995) observed similarincreased PTPase activity in the livers of obese, diabetic ob/ob mice, agenetic rodent model of NIDDM.

The compounds of this invention have been shown to inhibit PTPasesderived from rat liver microsomes and human-derived recombinantPTPase-1B (hPTP-1B) in vitro. They are useful in the treatment ofinsulin resistance associated with obesity, glucose intolerance,diabetes mellitus, hypertension and ischemic diseases of the large andsmall blood vessels.

K. Shinzo, et al., Heterocylces 1982, 19, 1033-1037 disclosed asynthesis of benzo[b]naphtho[2,3-d]thiophenes of which two examples alsohad a 11-phenyl substituent as shown by structure A below. The compoundsshown by structure A differ from that in the present invention in thatthe terminal furan ring of the compounds in the present invention isreplaced by a benzene ring. None of these prior art compounds are forthe indications of diabetes or PTPase inhibitors. ##STR2##

DESCRIPTION OF THE INVENTION

This invention provides compounds of Formula I having the structure##STR3## wherein B and D are each, independently, hydrogen, halogen,--CN, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;

R¹ is hydrogen, alkyl of 1-6 carbon atoms, --CH(R²)W, --C(CH₃)₂ CO₂ R³,5-thiazolidine-2,4-dione, --CH(R⁴)CH₂ CO₂ R³, --COR³, or --PO₃ (R³)₂ ;

R² is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms,aryl, --CH₂ (1H-imidazol-4-yl), --CH₂ (3-1H-indolyl), --CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), --CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), or --CH₂ (3-pyridyl);

W is --CO₂ R³, --CONH₂, --CONHOH, --CN, CONH(CH₂)₂ CN, 5-tetrazole, or--PO₃ (R³)₂ ;

R³ is hydrogen, alkyl of 1-6 carbon atoms, or aryl;

R⁴ is hydrogen or alkyl of 1-6 carbon atoms;

or a pharmaceutically acceptable salt thereof, which are useful intreating metabolic disorders related to insulin resistance orhyperglycemia.

Pharmaceutically acceptable salts can be formed from organic andinorganic acids, for example, acetic, propionic, lactic, citric,tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic,camphorsulfonic, and similarly known acceptable acids when a compound ofthis invention contains a basic moiety, such as when R² is CH₂(3-pyridyl) or contains similar basic moieties. Salts may also be formedfrom organic and inorganic bases, preferably alkali metal salts, forexample, sodium, lithium, or potassium, when a compound of thisinvention contains a carboxylate or phenolic moiety.

Alkyl includes both straight chain as well as branched moieties. Halogenmeans bromine, chlorine, fluorine, and iodine. It is preferred that thearyl portion of the aryl or aralkyl substituent is a phenyl or naphthyl;with phenyl being most preferred. The aryl moiety may be optionallymono-, di-, or tri-substituted with a substituent selected from thegroup consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbonatoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbon atoms,alkylamino of 1-6 carbon atoms, and dialkylamino in which each of thealkyl groups is of 1-6 carbon atoms, nitro, cyano, --CO₂ H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms.

The compounds of this invention may contain an asymmetric carbon atomand some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof.

The compounds of this invention may be atropisomers by virtue ofpossible restricted or slow rotation about the aryl-tetracyclic singlebond. This restricted rotation creates additional chirality and leads toenantiomeric forms. If there is an additional chiral center in themolecule, diasteriomers exist and can be seen in the NMR and via otheranalytical techniques. While shown without respect to atropisomerstereochemistry in Formula I, the present invention includes suchatoropisomers (enantiomers and diastereomers; as well as the racemic,resolved, pure diastereomers and mixutures of diasteomers) andpharmaceutically acceptable salts thereof.

Preferred compounds are those in which B and D are halogen; those inwhich R¹ is hydrogen or --CH(R²)W; and those in which R¹ is hydrogen or--CH(R²)W, wherein R² is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of6-12 carbon atoms, or aryl, W is --CO₂ R³, or CONH₂, and R³ is hydrogen,or alkyl of 2-6 carbon atoms. More preferred compounds of this inventionare:

((R)-2-[4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-3-phenyl-propionicacid; and

(R)-2-[4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-propionicacid.

The compounds of this invention can be prepared according to thefollowing schemes from commercially available starting materials orstarting materials which can be prepared using to literature procedures.These schemes show the preparation of representative compounds of thisinvention. ##STR4##

In Scheme 1, commercially available thianaphthene (IIa) is treated withone to 1.3 molar equivalents of an alkyl lithium reagent such as N-butyllithium most preferably in a nonprotic solvent such as THF attemperatures ranging from -78° C. to room temperature under an inertatmosphere such as nitrogen or argon to provide the2-lithiated-thianaphthene derivative. This lithiated analog is reactedin situ with one or more molar equivalents of4,5-dimethyl-2-furanaldehyde (IIb) (prepared from Vilsmeir-Haackformylation of commercially available 4,5-dimethylfuraldehyde; S. F.Martin, et al. J. Org. Chem. 1984, 49, 2512-2516), generally at -78° C.to room temperature for 5 min to 3 h to provide the compound of formula(III: Q═OH). The hydroxy group (Q═OH) of (III) can be removed by anumber of reduction procedures such as hydrogenation using palladiumcatalysts to produce the compound of formula (III: Q═H) but is mostconveniently removed using a modification of the method of Nutaitis, et.al. (Org. Prep. and Proceed. Int. 1991, 23, 403-411) in which (III:Q═OH) is stirred with one to ten molar equivalents of sodium borohydridein a suitable solvent such as ether, THF, dichloromethane or carbondisulfide at 0° C. to room temperature and one to fifty molarequivalents of trifluoroacetic acid is slowly added over a 15 min to 3 hperiod to produce the compound of formula (III: Q═H).

The compounds of formula (III: Q═H) can be reacted with one or moremolar equivalents of a commercially available benzoic acid chloride offormula (IV: B, D is H) to produce the cyclic derivative of formula (Ia:B, D is H). This reaction is accomplished most readily using a one tofive molar equivalents of a Lewis acid catalyst such as tintetrachloride or aluminum chloride in an inert solvent such asdichloromethane, 1, 2-dichloroethane, ether or carbon disulfide,generally at temperatures ranging from -78° C. to room temperature.

In an analogous fashion to the reactions above in Scheme 1, thecompounds of formula (Ia: B, D is lower alkyl) can be prepared startingfrom the compound of formula (III: Q is H) and the appropriate benzoicacid chloride (IV: B, D is lower alkyl). The benzoic acid chloride (IV:B, D is lower alkyl). is prepared from the corresponding benzoic acid bystandard procedures using reagents such as oxalyl chloride and thionylchloride. The starting benzoic acid of the benzoic acid chloride (IV: B,D is lower alkyl) is commercially available or can be easily prepared byknown procedures. For example, the acid starting material for benzoicacid chloride (IV: B, D is isopropyl) can be prepared using amodification of the method of Schuster, et al., J. Org. Chem 1988, 53,5819. Thus commercially available 2, 6-diisopropyl phenol is brominatedin the 4-position (bromine/acetic acid), methylated(iodomethane/potassium carbonate/DMF), reacted with n-butyl lithium toeffect lithium halogen exchange and the resultant organolithium speciesis reacted with carbon dioxide to provide 3, 5-diisopropyl, 4-methoxybenzoic acid.

The methyl ethers of formula (Ia: B, D is H, lower alkyl) can bedemethylated to the phenols of formula (Ia': B, D is H, lower alkyl)using standard demethylation procedures including one or more molarequivalents of boron tribromide or boron trichloride in dichloromethaneat -78° C. to room temperature; excess neat pyridinium hydrochloride at190 to 280° C.; hydrobromic acid in acetic acid at 0° C. to 50° C.;excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane,carbon tetrachloride or acetonitrile at -78° C. to 50° C.; lithiumiodide in pyridine or quinoline at temperatures from 100° to 250° C. andone or more molar equivalents of ethyl, methyl or isopropyl mercaptan inthe presence of one or more molar equivalents of a Lewis acid such asaluminum trichloride or boron trifluoride in a solvent such asdichloromethane at temperatures ranging from -78° C. to 50° C. ##STR5##

The phenol of formula (Ib) (Scheme 2) can be conveniently iodinated tothe diiodophenol of formula (Ic: B, D is I; R¹ is H) using at least twomolar equivalents of iodine in the presence of two or more molarequivalents of an alkali metal hydroxide such as NaOH in an alcoholsolvent such as methanol at -20° C. to room temperature. Similarly themonoiodophenol (Ic: B is I; R¹, D is H) can be prepared from the phenolof formula (Ib) (Scheme 2) using one to 1.5 molar equivalents of iodinein the presence of at least one equivalent of an alkali metal hydroxidesuch as NaOH in an alcohol solvent such as methanol at -20° C. to roomtemperature. Either the monoiodophenol (Ic: B is I; R¹, D is H) or thediiodophenol (Ic: B, D is I; R¹ is H) can be converted to the respectivemethyl ether derivative of formula (Ic: B is I; D is H; R¹ is Me) or(Ic: B, D is I; R¹ is Me) by reacting the phenol moiety with a suitablemethylating agent such as one or more molar equivalents of methyl iodideor dimethylsulfate employing a base such an alkali methyl carbonate orhydroxide such as potassium carbonate or sodium hydroxide in a suitablesolvent such as THF, DMF or DMSO. The reaction is generally performed attemperatures ranging from 0° C. to 60° C.

The monoiodo methylether derivative of formula (Ic: B is I; D is H; R¹is Me) or the diiodo methylether of formula (Ic: B, D is I; R¹ is Me)can be reacted with one or more molar equivalents of copper (I) cyanidefor the monoiodo analog or two or more molar equivalents of copper (I)cyanide for the diiodo derivative to produce the monocyanomethyl etherof formula (Ib: B is CN; D is H; R¹ is Me) or the dicyanomethyl ether offormula (Ib: B, D is CN; R¹ is Me). The cyanation reaction is generallyperformed at temperatures ranging from 100° C. to 250° C. employingpolar aprotic solvents such as DMF, 1-methyl-2-pyrrolidinone or HMPA.Quinoline or pyridine can also be used.

The mono or dicyano methoxy analogs of formula (Ib: B is CN; D is H orCN; R¹ is Me) can be converted to the corresponding mono or dicyanophenol analogs of formula (Ic: B is CN; D is H or CN; R¹ is H) (Scheme2) using standard demethylation procedures including one or more molarequivalents of boron tribromide or boron trichloride in dichloromethaneat -78° C. to room temperature; excess neat pyridinium hydrochloride at190 to 280° C.; hydrobromic acid in acetic acid at 0° C. to 50° C.;excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane,carbon tetrachloride or acetonitrile at -78° C. to 50° C.; lithiumiodide in pyridine or quinoline at temperatures from 100° to 250° C. andone or more molar equivalents of ethyl, methyl or isopropyl mercaptan inthe presence of one or more molar equivalents of a Lewis acid such asaluminum trichloride or boron trifluoride in a solvent such asdichloromethane at temperatures ranging from -78° C. to 50° C.

The monoiodo methylether derivative of formula (Ic: B is I; D is H; R¹is Me) or the diiodo methylether of formula (Ic: B, D is I; R¹ is Me)(Scheme 2) can be reacted with one or more molar equivalents of copper(I) bromide for the monoiodo analog or two or more molar equivalents ofcopper (I) bromide for the diiodo derivative to produce the monobromomethyl ether of formula (Ic: B is Br; D is H; R¹ is Me) or thedibromo-methyl ether of formula (Ic: B, D is Br; R¹ is Me). Thebromine/idodine exchange reaction is generally performed at temperaturesranging from 100° C. to 250° C. employing polar aprotic solvents such asDMF, 1-methyl-2-pyrrolidinone or HMPA. Quinoline or pyridine can also beused. The mono or dibromo methoxy analogs of formula (Ib: B is Br; D isH or Br; R¹ is Me) can be converted to the corresponding mono or dibromophenol analogs of formula (Ib: B is Br; D is H or Br; R¹ is H) (Scheme2) using standard demethylation procedures including one or more molarequivalents of boron tribromide or boron trichloride in dichloromethaneat -78° C. to room temperature; excess neat pyridinium hydrochloride at190 to 280° C.; hydrobromic acid in acetic acid at 0° C. to 50° C.;excess trimethylsilylbromide or trimethylsilyliodide in dichloromethane,carbon tetrachloride or acetonitrile at -78° C. to 50° C.; lithiumiodide in pyridine or quinoline at temperatures from 100° to 250° C. andone or more molar equivalents of ethyl, methyl or isopropyl mercaptan inthe presence of one or more molar equivalents of a Lewis acid such asaluminum trichloride or boron trifluoride in a solvent such asdichloromethane at temperatures ranging from -78° C. to 50° C.

The phenols of formula (Ib: B, D is H, Br, I, CN, lower alkyl; R¹ is H)can be acylated on the phenolic oxygen using one or more molarequivalents of suitable acylating agent to provide the compounds offormula (Ib: B, D is H, Br, I, CN, lower alkyl; R¹ is OCOR; R is loweralkyl, aryl). The acylating agent is generally a lower alkyl or arylcarboxylic acid anhydride or a lower alkyl or aryl carboxylic acidchloride. The reaction is run under standard conditions such as usingpyridine as solvent with or without a co-solvent such as dichloromethaneat 0° C. to room temperature. ##STR6##

Further derivatives of the compounds of formula (I) in Scheme 3 can beprepared by the following methods. The phenols of formula (Id: B, D isH, Br, I, CN, lower alkyl) can be alkylated with one or more molarequivalents of an alkyl haloacetate of formula (X² CH₂ CO₂ R³ where X²is Cl, Br or I and R³ is lower alkyl) and with one or more molarequivalents of an alkali metal carbonate such as potassium carbonate ina polar aprotic solvent such as DMF to afford the alkylated product offormula (Ie: B, D is H, Br, I, CN, lower alkyl; W is CO₂ R³ ; R³ is H;R³ is lower alkyl).

The phenols of formula (Id: B, D is H, Br, I, CN, lower alkyl) can bereacted with a 2-hydroxy carboxylic acid ester of formula CH(OH)(R²)CO₂R³ (R² is H, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl), CH₂(3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl); R³ is lower alkyl)to afford the esters of formula (Ie: B, D is H, Br, I, CN, lower alkyl;W is CO₂ R³ ; R² is H, lower alkyl, aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂ (3-1 H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl); R³ is lower alkyl)under the conditions of the Mitsunobu Reactions (for a review see OyoMitsunobu Synthesis. 1981, 1-27). The other co-reagents necessary toeffect the Mitsunobu Reaction include one or more molar equivalents of alower alkyl azodicarboxylate diester such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate and one or more molar equivalents oftriarylphosphine such as triphenylphosphine in a suitable solvent suchas diethyl ether, THF, benzene or toluene at temperatures ranging from-20° C. to 120° C.

The 2-hydroxy carboxylic acid ester of formula CH(OH)(R²)CO₂ R³ (R² isH, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl), CH₂(3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl); R³ is lower alkyl)are commercially available or can be prepared from commerciallyavailable carboxylic acid precursors under standard esterificationconditions. (S)-(+)-2-Hydroxy-1-oxo-3-dihydro-2-isoindolinebutyric acid,methyl ester can be prepared from(S)-(+)-2-hydroxy-1,3-dioxo-2-isoindolinebutyric acid, methyl ester viasequential treatment with 1) sodium borohydride in THF-water; 2)trifluoroacetic acid/chloroform; 3) triethylsilane/trifluoroacetic acidand 4) aqueous sodium bicarbonate. 3-(Pyridin-3-yl)-phenyllactic acid,ethyl ester can be prepared according to the two step procedure of B. A.Lefker, W. A. Hada, P. J. McGarry Tetrahedron Lett. 1994, 35, 5205-5208,from commercially available 3-pyridinecarboxaldehyde and ethylchloroacetate.

The esters of formula (Ie: B, D is H, Br, I, CN, lower alkyl; W is CO₂Btu; R² is H) can be treated with one or more molar equivalents of astrong base such as lithium diisopropyl amide in a suitable solvent suchas THF at temperatures ranging from -78° C. to room temperature. Thisprocedure produces an anion alpha to the ester carbonyl. The resultantanion is treated with one or more molar equivalents of an alkyl halideof formula X² R² (where X² is halogen; R² is alkyl and aralkyl) andwarmed to room temperature to produce the alkylated ester of formula(Ie: B, D is H, Br, I, CN, lower alkyl; W is CO₂ tBu; R² is alkyl andaralkyl).

The esters of formula (Ie: B, D is H, Br, I, CN, lower alkyl; W is CO₂R³ ; R² is H, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl), CH₂(3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl); R³ is lower alkyl)can be transformed into their carboxylic acid analogs using standardconditions to afford the carboxylic acids of formula (Ie: B, D is H, Br,I, CN, lower alkyl; W is CO₂ H; R² is H, lower alkyl, aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂ (3-1H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)). The conditions toeffect these transformations include aqueous base in which one or moremolar equivalents of alkali metal hydroxide such as sodium hydroxide isused in water with a co-solvent such as THF, dioxane or a lower alcoholsuch as methanol or mixtures of THF and a lower alcohol at temperaturesranging from 0° C. to 40° C. Alternatively, acid conditions may also beemployed in which the above mentioned carboxylic acid ester of formula(Ie) is reacted with one or more molar equivalents of a mineral acidsuch as HCl or sulfuric acid in water with or without a co-solvent suchas THF at temperatures ranging from room temperature to 80° C. Stillalternatively, many other conditions may be employed to effect the abovementioned ester to acid transformation leading to (Ie). These includereacting the carboxylic acid ester of formula (Ie) with one or moremolar equivalents of boron tribromide or boron trichloride indichloromethane at -78° C. to room temperature; one or more molarequivalents hydrobromic acid in acetic acid at 0° C. to 50° C.; one ormore molar equivalents trimethylsilylbromide or trimethylsilyliodide indichloromethane, carbon tetrachloride or acetonitrile at -78° C. to 50°C.; one or more molar equivalents lithium iodide in pyridine orquinoline at temperatures from 100° to 250° C.

The phenols of formula (Id: B, D is H, Br, I, CN, lower alkyl) can bealkylated with one or more molar equivalents of diethyl trifluoromethylsulfonyloxy methylphosphanate (D. P. Phillion and S. S. Andrew Tet.Lett. 1986, 1477-1480) and with one or more molar equivalents of analkali metal hydride such as sodium hydride in a suitable solvent suchas THF or DMF to afford the diethylphosphonate product of formula (Ie:B, D is H, Br, I, CN, lower alkyl; W is PO₃ Et₂ ; R² is H).

The phenols of formula (Id: B, D is H, Br, I, CN, lower alkyl) can bereacted with a 2-hydroxy phosphonic acid diester of formulaCH(OH)(R²)PO₃ (R³)₂, (R² is H, lower alkyl, aralkyl, aryl, R³ is loweralkyl)) to afford the phosphonic acid diesters of formula (Ie: B, D isH, Br, I, CN, lower alkyl; W is PO₃ (R³)₂ ; R² is H, lower alkyl,aralkyl, aryl, R³ is lower alkyl) under the conditions of the MitsunobuReactions (for a review see Oyo Mitsunobu Synthesis 1981, 1-27). Theother co-reagents necessary to effect the Mitsunobu Reaction include oneor more molar equivalents of a lower alkyl azodicarboxylate diester suchas diethyl azodicarboxylate or diisopropyl azodicarboxylate and one ormore molar equivalents of triarylphosphine such as triphenylphosphine ina suitable solvent such as diethyl ether, THF, benzene or toluene attemperatures ranging from -20° C. to 120° C.

The 2-hydroxy phosphonic acid diester of formula CH(OH)(R²)PO₃ R³ (R² isH, lower alkyl, aralkyl, aryl; R³ is lower alkyl) can be prepared byreacting a dialklylphosphonate of formula HP(O)(OR³)₂ (R³ is loweralkyl) with an aldehyde of formula R² CHO (R² is lower alkyl, aryl,aralkyl) under standard conditions.

The phosphonic acid diesters of formula (Ie: B, D is H, Br, I, CN, loweralkyl; W is PO₃ (R³)₂ ; R² is H, lower alkyl, aralkyl, aryl, R³ is loweralkyl) can be transformed into their phosphonic acid analogs usingstandard conditions to afford the phosphonic acids of formula (Ie: B, Dis H, Br, I, CN, lower alkyl; W is PO₃ H₂ ; R² is H, lower alkyl,aralkyl, aryl). The conditions that may also be employed in which theabove mentioned phosphonic acid diester of formula (Ie) is reacted withtwo or more molar equivalents of a mineral acid such as HCl or sulfuricacid in water with or without a co-solvent such as THF at temperaturesranging from 40 to 100° C. Still alternatively, many other conditionsmay be employed to effect the above mentioned diester to acidtransformation leading to (Ie). These include reacting the phosphonicacid diester of formula (Ie) with two or more molar equivalents of borontribromide or boron trichloride in dichloromethane at -78° C. to roomtemperature; two or more molar equivalents hydrobromic acid in aceticacid at 0° C. to 50° C.; two or more molar equivalentstrimethylsilylbromide or trimethylsilyliodide in dichloromethane, carbontetrachloride or acetonitrile at -78° C. to 50° C.; two or more molarequivalents lithium iodide in pyridine or quinoline at temperatures from60° to 250° C.

The esters of formula (Ie: B, D is H, Br, I, CN, lower alkyl; W is CO₂R³ ; R² is H, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl), CH₂(3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl); R⁴ is lower alkyl)can be transformed into their primary carboxylic acid amide analogs offormula (Ie: B, D is H, Br, I, CN, lower alkyl; W is CONH₂ ; R² is H,lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl), CH₂ (3-1H-indolyl),CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) by reacting theester starting material with ammonia gas dissolved in a lower alcoholsolvent such as methanol or ethanol at temperatures ranging from 0° C.to 100° C. Alternatively, the carboxylic acids of formula (Ie: B, D isH, Br, I, CN, lower alkyl; W is CO₂ H; R² is H, lower alkyl, aralkyl,aryl, CH₂ (1H-imidazol-4-yl), CH₂ (3-1H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) can be transformedinto their carboxylic acid amide analogs of formula (Ie: B, D is H, Br,I, CN, lower alkyl; W is CONH₂ ; R² is H, lower alkyl, aralkyl, aryl,CH₂ (1H-imidazol-4-yl), CH₂ (3-1H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)). This transformationcan be accomplished using standard methods to effect carboxylic acid tocarboxylic acid amide transformations. These methods include convertingthe acid to an activated acid and reacting with one or more molarequivalents of the desired amine. Amines in this category includeammonia in the form of ammonium hydroxide, hydroxyl amine and2-aminopropionitrile. Methods to activate the carboxylic acid includereacting said acid with one or more molar equivalents of oxalyl chlorideor thionyl chloride to afford the carboxylic acid chloride in a suitablesolvent such as dichloromethane, chloroform or diethyl ether. Thisreaction is often catalyzed by adding small amounts (0.01 to 0.1 molarequivalents) of dimethylformamide. Other methods to activate thecarboxylic acid include reacting said acid with one or more molarequivalents dicyclohexylcarbodiimide with or without one or more molarequivalents of hydroxybenzotriazole in a suitable solvent such asdichloromethane or dimethylformamide at temperatures ranging from 0° C.to 60° C.

The phenols of formula (Id: B, D is H, Br, I, CN, lower alkyl) can bealkylated with one or more molar equivalents of a haloacetonitrile offormula (X² CH₂ CN where X² is Cl, Br or I) and with one or more molarequivalents of an alkali metal carbonate such as potassium carbonate ina polar aprotic solvent such as DMF to afford the nitriles of formula(Ie: B, D is H, Br, I, CN, lower alkyl W is CN; R² is H).

Alternatively, the carboxylic acid amide analogs of formula (Ie: B, D isH, Br, I, CN, lower alkyl; W is CONH₂ ; R² is H, lower alkyl, aralkyl,aryl, CH₂ (1H-imidazol-4-yl), CH₂ (3-1H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) can be converted totheir nitrile analogs of formula (Ie: B, D is H, Br, I, CN, lower alkyl;W is CN; R² is H, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl),CH₂ (3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂CH₂ (1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) by usingreagents that dehydrate the primary carboxamide function to the nitrilefunction. One set of conditions to effect this transformation includereacting the said primary carboxylic acid amide with one or more molarequivalents of trifluoroacetic anhydride and two or more molarequivalents of pyridine in a suitable solvent such as dioxane attemperatures ranging from 60° C. to 120° C.

The nitriles analogs of formula (Ie: B, D is H, Br, I, CN, lower alkyl;W is CN; R² is H, lower alkyl, aralkyl, aryl, CH₂ (1H-imidazol-4-yl),CH₂ (3-1H-indolyl), CH₂ CH₂ (1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂CH₂ (1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) can be convertedto the tetrazoles of formula (Ie: B, D is H, Br, I, CN, lower alkyl; Wis 5-tetrazole; R² is H, lower alkyl, aralkyl, aryl, CH₂(1H-imidazol-4-yl), CH₂ (3-1 H-indolyl), CH₂ CH₂(1,3-dioxo-1,3-dihydro-isoindol-2-yl), CH₂ CH₂(1-oxo-1,3-dihydro-isoindol-2-yl), CH₂ (3-pyridyl)) by reacting thenitrile function with one or more molar equivalents of trimethylaluminumand one or more molar equivalents of trimethylsilyl azide in a suitablesolvent such as benzene or toluene at temperatures ranging from 60° C.to 120° C. Alternatively, the nitrile function can be reacted with oneor more molar equivalents of ammonium azide in a suitable solvent suchas dimethylformamide at temperatures ranging from 60° C. to 160° C.##STR7##

Further derivatives of the compounds of formula (I) in Scheme 4 can beprepared by the following methods. The phenols of formula (If: B, D isH, Br, I, CN, lower alkyl) can be reacted with one or more molarequivalents of lithium (bis)trimethylsilylamide at temperatures rangingfrom -78° C. to room temperature and the lithium salt can be furtherreacted with one or more molar equivalents of 5-bromothiazolidine-2,4-dione (prepared according to the method of Zask, et al., J. Med Chem,1990, 33, 1418-1423) using a suitable solvent such as THF under an inertatmosphere at temperatures ranging from -78° C. to room temperature toprovide the compounds of formula (Ig: R¹ is (R,S)-5-thiazolidine-2,4-dione; B, D is H, Br, I, CN, lower alkyl).

Alternatively, the phenols of formula (If: B, D is H, Br, I, CN, loweralkyl) can be reacted with one or more molar equivalents of tetrazoleand di-tert-butyl N,N-diethylphosporamidate in THF at room temperaturefollowed by addition of one or more molar equivalents ofmeta-chlorobenzoic acid at -40° C. according to the procedure of J. W.Perich and R. B. Johns, Synthesis, 1988, 142-144) to afford thephosphate diesters of formula (Ig: R¹ is P(O)(OtBu)₂ ; B, D is H, Br, I,CN, lower alkyl). These phosphate diesters are then treated with one ormore molar equivalents hydrochloric acid in a suitable solvent such asdioxane to provide the phosphonic acids of formula (Ig: R¹ is P(O)(OH)₂; B, D is H, Br, I, CN, lower alkyl).

The phenols of formula (If: B, D is H, Br, I, CN, lower alkyl) can betransformed to the carboxylic acids of formula (Ig: R¹ is C(CH₃)₂ CO₂ H;B, D is H, Br, I, CN, lower alkyl) by treatment of the phenols with twoor more molar equivalents of solid sodium hydroxide followed by one ormore molar equivalents of 1,1,1 -trichloro-2-methyl-2-propanoltetrahydrate in the presence of a large excess of acetone which alsoserves as solvent.

The phenols of formula (If: B, D is H, Br, I, CN, lower alkyl) can betransformed to the carboxylic acids of formula (Ig: R¹ is CH₂ CH₂ CO₂ H;B, D is H, Br, I, CN, lower alkyl) by treatment with one or more molarequivalents of β-propiolactone and treatment with one or more molarequivalents of potassium tert-butoxide in a suitable solvent such asTHF.

The phenols of formula (If: B, D is H, Br, I, CN, lower alkyl) can bereacted with a 3-hydroxy carboxylic acid ester of formula CH(OH)(R⁴)H₂CO₂ R³ (R⁴ is H or lower alkyl; R³ is lower alkyl) to afford the estersof formula (Ig: R¹ is (R)--CH(R⁴)CH₂ CO₂ R³ ; B, D is H, Br, I, CN,lower alkyl; R⁴ is H or lower alkyl; R³ is lower alkyl) under theconditions of the Mitsunobu Reactions (for a review see Oyo MitsunobuSynthesis 1981, 1-27). The other co-reagents necessary to effect theMitsunobu Reaction include one or more molar equivalents of a loweralkyl azodicarboxylate diester such as diethyl azodicarboxylate ordiisopropyl azodicarboxylate and one or more molar equivalents oftriarylphosphine such as triphenylphosphine in a suitable solvent suchas diethyl ether, THF, benzene or toluene at temperatures ranging from-20° C. to 120° C. at temperatures ranging from -20° C. to 120° C.

The 3-hydroxy carboxylic acid ester of formula CH(OH)(R⁴)CH₂ CO₂ R³ (R⁴is H or lower alkyl; R³ is lower alkyl) are commercially available orcan be prepared from commercially available carboxylic acid precursorsunder standard esterification conditions.

The esters of formula (Ig: R¹ is (R)--CH(R⁴)CH₂ CO₂ R³ ; B, D is H, Br,I, CN, lower alkyl; R⁴ is H or lower alkyl; R⁴ is lower alkyl) can betransformed to the acids of formula (Ig: R¹ is (R)--CH(R⁴⁴)CH₂ CO₂ H; B,D is H, Br, I, CN, lower alkyl; R⁴ is H or lower alkyl) by severalstandard conditions which include reacting the ester of formula (Ig)with two or more molar equivalents of a mineral acid such as HCl orsulfuric acid in one or more solvents or a combination of two or moresolvents such as water, THF or dioxane at temperatures ranging from 40to 120° C. Still alternatively, many other conditions may be employed toeffect the above mentioned ester to acid transformation leading to (Ig).These include reacting the esters of formula (Ig) with two or more molarequivalents of boron tribromide or boron trichloride in dichloromethaneat -78° C. to room temperature; two or more molar equivalentshydrobromic acid in acetic acid at 0° C. to 50° C.; two or more molarequivalents trimethylsilylbromide or trimethylsilyliodide indichloromethane, carbon tetrachloride or acetonitrile at -78° C. to 50°C.; two or more molar equivalents lithium iodide in pyridine orquinoline at temperatures from 60° to 250° C.

The compounds of this invention are useful in treating metabolicdisorders related to insulin resistance or hyperglycemia, typicallyassociated with obesity or glucose intolerance. The compounds of thisinvention are therefore, particularly useful in the treatment orinhibition of type II diabetes. The compounds of this invention are alsouseful in modulating glucose levels in disorders such as type Idiabetes.

The ability of compounds of this invention to treat or inhibit disordersrelated to insulin resistance or hyperglycemia was established withrepresentative compounds of this invention in the following two standardpharmacological test procedures which measure the inhibition of PTPase.

Inhibition of tri-phosphorylated insulin receptor dodecaphosphopeptidedephosphorylation by rat hepatic protein-tyrosine phosphatases (PTPases)

This standard pharmacological test procedure assess the inhibition ofrat hepatic microsomal PTPase activity using, as substrate, thephosphotyrosyl dodecapeptide corresponding to the 1142-1153 insulinreceptor kinase domain, phosphorylated on the 1146, 1150 and 1151tyrosine residues. The procedure used and results obtained are brieflyoutlined below.

Preparation of Microsomal Fraction: Rats (Male Sprague-Dawley rats(Charles River, Kingston, N.Y.) weighing 100-150 g, maintained onstandard rodent chow (Purina)) are sacrificed by asphyxiation with CO2and bilateral thoracotomy. The liver is removed and washed in cold 0.85%(w/v) saline and weighed. The tissue is homogenized on ice in 10 volumesof Buffer A and the microsomes are isolated essentially as described byMeyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, Kahn CR.Vanadate normalizes hyperglycemia in two mouse models ofnon-insulin-dependent diabetes mellitus. J Clin Invest 1991;87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, WatsonJD, editors. Molecular biology of the cell. New York: GarlandPublishing, Inc., 1989 with minor modifications. The liver homogenate isfiltered through silk to remove any remaining tissue debris and then iscentrifuged at 10,000×g for 20 minutes at 40 C. The supernatant isdecanted and centrifuged at 100,000×g for 60 minutes at 40 C. Thepellet, microsomes and small vesicles, is resuspended and lightlyhomogenized in: 20 mM TRIS-HCl (pH 7.4), 50 mM 2-mercaptoethanol, 250 mMsucrose, 2 mM EDTA, 10 mM EGTA, 2 mM AEBSF, 0.1 mM TLCK, 0.1 mM TPCK,0.5 mM benzamidine, 25 ug/ml leupeptin, 5 ug/ml pepstatin A, 5 ug/ml;H5Bantipain, 5 ug/ml chymostatin, 10 ug/ml aprotinin (Buffer A), to a finalconcentration of approximately 850 ug protein/ml. Protein concentrationis determined by the Pierce Coomassie Plus Protein Assay usingcrystalline bovine serum albumin as a standard (Pierce Chemical Co.,Rockford, Ill.).

Measurement of PTPase activity: The malachite green-ammonium molybdatemethod, as described by Lanzetta PA, Alvarez LJ, Reinach PS, Candia OAwas used. An improved assay for nanomolar amounts of inorganicphosphate. Anal. Biochem. 1979;100:95-97, and adapted for theplatereader, is used for the nanomolar detection of liberated phosphateby rat hepatic microsomal PTPases. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). The peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150 and 1151 tyrosine residues. Themicrosomal fraction (83.25 ul) is preincubated for 10 min at 37 deg.Cwith or without test compound (6.25 ul) and 305.5 ul of the 81.83 mMHEPES reaction buffer, pH 7.4. Peptide substrate, 10.5 ul at a finalconcentration of 50 uM, is equilibrated to 37 deg.C in a LABLINEMulti-Blok heater equipped with a titerplate adapter. The preincubatedmicrosomal preparation (39.5 ul) with or without drug is added toinitiate the dephosphorylation reaction, which proceeds at 37 deg.C for30 min. The reaction is terminated by the addition of 200 ul of themalachite green-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw).The stopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 ulMG/AM/Tw to substrate and followed by 39.5 ul of the preincubatedmembrane with or without drug. The color is allowed to develop at roomtemperature for 30 min and the sample absorbances are determined at 650nm using a platereader (Molecular Devices). Samples and blanks areprepared in quadruplicates. Screening activity of 50 uM (final) drug isaccessed for inhibition of microsomal PTPases.

Calculations: PTPase activities, based on a potassium phosphate standardcurve, are expressed as nmoles of phosphate released/min/mg protein.Test compound PTPase inhibition is calculated as percent of control. Afour parameter non-linear logistic regression of PTPase activities usingSAS release 6.08, PROC NLIN, is used for determining IC50 values of testcompounds. All compounds were administered at a concentration of 50 μM.The following results were obtained using representative compounds ofthis invention.

    ______________________________________                                                        % Change from                                                 Example         Control                                                       ______________________________________                                        8               -58.84                                                        9               -72.70                                                        Phenylarsine oxide                                                                            -57.06                                                        (reference standard)                                                          ______________________________________                                    

Inhibition of Tri-Phosphorylated Insulin Receptor DodecaphosphopeptideDephosphorylation by hPTP1B

This standard pharmacological test procedure assess the inhibition ofrecombinant rat protein tyrosine phosphatase, PTP1B, activity using, assubstrate, the phosphotyrosyl dodecapeptide corresponding to the1142-1153 insulin receptor kinase domain, phosphorylated on the 1146,1150 and 1151 tyrosine residues. The procedure used and results obtainedare briefly described below.

Human recombinant PTP1B was prepared as described by Goldstein (seeGoldstein et al. Mol. Cell. Biochem. 109, 107, 1992). The enzymepreparation used was in microtubes containing 500-700 μg/ml protein in33 mM Tris-HCl, 2 mM EDTA, 10% glycerol and 10 mM 2-mercaptoethanol.

Measurement of PTPase activity. The malachite green-ammonium molybdatemethod, as described (Lanzetta et al. Anal Biochem. 100, 95, 1979) andadapted for a platereader, is used for the nanomolar detection ofliberated phosphate by recombinant PTP1B. The test procedure uses, assubstrate, a dodecaphosphopeptide custom synthesized by AnaSpec, Inc.(San Jose, Calif.). the peptide, TRDIYETDYYRK, corresponding to the1142-1153 catalytic domain of the insulin receptor, is tyrosinephosphorylated on the 1146, 1150, and 1151 tyrosine residues. Therecombinant rPTP1B is diluted with buffer (pH 7.4, containing 33 mMTris-HCl, 2 mM EDTA and 50 mM b-mercaptoethanol) to obtain anapproximate activity of 1000-2000 nmoles/min/mg protein. The dilutedenzyme (83.25 mL) is preincubated for 10 min at 37° C. with or withouttest compound (6.25 mL) and 305.5 mL of the 81.83 mM HEPES reactionbuffer, pH 7.4 peptide substrate, 10.5 ml at a final concentration of 50mM, and is equilibrated to 37° C. in a LABLINE Multi-Blok heaterequipped with a titerplate adapter. The preincubated recombinant enzymepreparation (39.5 ml) with or without drug is added to initiate thedephosphorylation reaction, which proceeds at 37° C. for 30 min. Thereaction is terminated by the addition of 200 mL of the malachitegreen-ammonium molybdate-Tween 20 stopping reagent (MG/AM/Tw). Thestopping reagent consists of 3 parts 0.45% malachite greenhydrochloride, 1 part 4.2% ammonium molybdate tetrahydrate in 4 N HCland 0.5% Tween 20. Sample blanks are prepared by the addition of 200 mLMG/AM/Tw to substrate and followed by 39.5 ml of the preincubatedrecombinant enzyme with or without drug. The color is allowed to developat room temperature for 30 min. and the sample absorbances aredetermined at 650 nm using a platereader (Molecular Devices). Sample andblanks are prepared in quadruplicates.

Calculations: PTPase activities, based on a potassium phosphate standardcurve, are expressed as nmoles of phosphate released/min/mg protein.Inhibition of recombinant PTP1B by test compounds is calculated aspercent of phosphatase control. A four parameter non-linear logisticregression of PTPase activities using SAS release 6.08, PROC NLIN, isused for determining IC₅₀ values of test compounds. The followingresults were obtained.

    ______________________________________                                        Example           IC.sub.50 (μM)                                           ______________________________________                                        8                 0.284                                                       9                 0.074                                                       Phenylarsine oxide                                                                              39.7                                                        (reference standard)                                                          Sodium orthovanadate                                                                            244.8                                                       (reference standard)                                                          Ammonium molybdate                                                                              8.7                                                         tetrahydrate                                                                  (reference standard)                                                          ______________________________________                                    

The blood glucose lowering activity of a representative compound of thisinvention was demonstrated in an in vivo standard procedure usingdiabetic (ob/ob) mice. The procedures used and results obtained arebriefly described below.

The non-insulin dependent diabetic (NIDDM) syndrome can be typicallycharacterizes by obesity, hyperglycemia, abnormal insulin secretion,hyperinsulinemia and insulin resistance. The geneticallyobese-hyperglycemic ob/ob mouse exhibits many of these metabolicabnormalities and is thought to be a useful model to search forhypoglycemic agents to treat NIDDM [Coleman, D.: Diabetologia 14:141-148, 1978].

In each test procedure, mice [Male or female ob/ob (C57 B1/6J) and theirlean litermates (ob/+ or +/+, Jackson Laboratories) ages 2 to 5 months(10 to 65 g)] of a similar age were randomized according to body weightinto 4 groups of 10 mice. The mice were housed 5 per cage and aremaintained on normal rodent chow with water ad libitum. Mice receivedtest compound daily by gavage (suspended in 0.5 ml of 0.5% methylcellulose); dissolved in the drinking water; or admixed in the diet. Thedose of compounds given ranges from 2.5 to 200 mg/kg body weight/day.The dose is calculated based on the fed weekly body weight and isexpressed as active moiety. The positive control, ciglitazone(5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-dione, see Chang, A., Wyse,B., Gilchrist, B., Peterson, T. and Diani, A. Diabetes 32: 830-838,1983.) was given at a dose of 100 mg/kg/day, which produces asignificant lowering in plasma glucose. Control mice received vehicleonly.

On the morning of Day 4, 7 or 14 two drops of blood (approximately 50ul) were collected into sodium fluoride containing tubes either from thetail vein or after decapitation. For those studies in which the compoundwas administered daily by gavage the blood samples were collected twohours after compound administration. The plasma was isolated bycentrifugation and the concentration of glucose is measuredenzymatically on an Abbott V.P. Analyzer.

For each mouse, the percentage change in plasma glucose on Day 4, 7 or14 is calculated relative to the mean plasma glucose of the vehicletreated mice. Analysis of variance followed by Dunett's Comparison Test(one-tailed) are used to estimate the significant difference between theplasma glucose values from the control group and the individual compoundtreated groups (CMS SAS Release 5.18).

The results shown in the table below shows that the compounds of thisinvention are antihyperglycemic agents as they lower blood glucoselevels in diabetic mice.

    ______________________________________                                                           % Change                                                                      Glucose from                                                                             % Change Insulin from                           Example Dose (mg/Kg)                                                                             Vehicle    Vehicle                                         ______________________________________                                        9       10         8.13 (a)   -43.43                                          Ciglitazone                                                                           100        -43        -39                                             (reference                                                                    standard                                                                      ______________________________________                                         (a) no significant activity (p < 0.05) at this dose.                          (b) not measured                                                         

Based on the results obtained in the standard pharmacological testprocedures, representative compounds of this invention have been shownto inhibit PTPase activity and lower blood glucose levels in diabeticmice, and are therefore useful in treating metabolic disorders relatedto insulin resistance or hyperglycemia, typically associated withobesity or glucose intolerance. More particularly, the compounds of thisinvention useful in the treatment or inhibition of type II diabetes, andin modulating glucose levels in disorders such as type I diabetes. Asused herein, the term modulating means maintaining glucose levels withinclinically normal ranges.

Effective administration of these compounds may be given at a dailydosage of from about 1 mg/kg to about 250 mg/kg, and may given in asingle dose or in two or more divided doses. Such doses may beadministered in any manner useful in directing the active compoundsherein to the recipient's bloodstream, including orally, via implants,parenterally (including intravenous, intraperitoneal and subcutaneousinjections), rectally, vaginally, and transdermally. For the purposes ofthis disclosure, transdermal administrations are understood to includeall administrations across the surface of the body and the inner liningsof bodily passages including epithelial and mucosal tissues. Suchadministrations may be carried out using the present compounds, orpharmaceutically acceptable salts thereof, in lotions, creams, foams,patches, suspensions, solutions, and suppositories (rectal and vaginal).

Oral formulations containing the active compounds of this invention maycomprise any conventionally used oral forms, including tablets,capsules, buccal forms, troches, lozenges and oral liquids, suspensionsor solutions. Capsules may contain mixtures of the active compound(s)with inert fillers and/or diluents such as the pharmaceuticallyacceptable starches (e.g. corn, potato or tapioca starch), sugars,artificial sweetening agents, powdered celluloses, such as crystallineand microcrystalline celluloses, flours, gelatins, gums, etc. Usefultablet formulations may be made by conventional compression, wetgranulation or dry granulation methods and utilize pharmaceuticallyacceptable diluents, binding agents, lubricants, disintegrants,suspending or stabilizing agents, including, but not limited to,magnesium stearate, stearic acid, talc, sodium lauryl sulfate,microcrystalline cellulose, carboxymethylcellulose calcium,polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum,sodium citrate, complex silicates, calcium carbonate, glycine, dextrin,sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose,kaolin, mannitol, sodium chloride, talc, dry starches and powderedsugar. Oral formulations herein may utilize standard delay or timerelease formulations to alter the absorption of the active compound(s).Suppository formulations may be made from traditional materials,including cocoa butter, with or without the addition of waxes to alterthe suppository's melting point, and glycerin. Water soluble suppositorybases, such as polyethylene glycols of various molecular weights, mayalso be used.

It is understood that the dosage, regimen and mode of administration ofthese compounds will vary according to the malady and the individualbeing treated and will be subject to the judgment of the medicalpractitioner involved. It is preferred that the administration of one ormore of the compounds herein begin at a low dose and be increased untilthe desired effects are achieved.

The following procedures describe the preparation of representativeexamples of this invention.

EXAMPLE 1

4.5-Dimethyl-2-furaldehyde

According to the procedure of S. F. Martin, et al. J. Org. Chem. 1984,49, 2512-2516, phosphorus oxychloride (10.7 mL, 114.4 mmol) was addeddropwise to a stirred, ambient temperature solution of 2,3-dimethylfuran(10 g, 104 mmol) in DMF (150 mL) under a dry nitrogen atmosphere over aperiod of 30 min. After 3 h., the reaction mixture was hydrolized with2.5 N aq. sodium hydroxide and further diluted with water (50 mL).Aqueous mixture was extracted with dichloromethane (2×300 mL). Thecombined dichloromethane extracts were washed with water, dried withbrine and purified by silica gel flash chromatography (eluent: ethylacetate) to provide a yellow oil (9.8 g, 76%); MS (ESI): [M+H]+, 125.1.

EXAMPLE 2

Benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methanol

n-Butyl lithium (2.5 N in hexanes, 32.2 mL, 80.5 mmol) was added to astirred solution of thianaphthene (10.6 g, 78.9 mmol) in THF (290 mL) at-78° C. After 15 min., a solution of 4,5-dimethyl-2-furaldehyde (9.79 g,78.9 mmol) in THF (10 mL) was added. After additional 1 hour, thereaction mixture was quenched with 10% aqueous ammonium chloride (150mL) and further diluted with water (150 mL). Aqueous mixture wasextracted with dichloromethane. The combined dichloromethane extractswere washed with water, dried with brine and anhydrous Na2SO4, andconcentrated to provide the title compound as an yellow oil (20.84 g,100%): NMR (DMSO-d6); δ7.89 (d, J=8 Hz, 1H), 7.76 (d, J=8, Hz, 1H),7.35-7.26 (m, 2H), 7.25 (s, 1H), 6.36 (s, 1H), 6.08 (s, 1H), 5.92 (s,1H), 2.13 (s, 3H), 1.86 (s, 3H); MS (EI): [M+], 258.

EXAMPLE 3

Benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5yl)-methane

Trifluoroacetic acid (30 mL) was added dropwise to a rt, stirredsuspension of benzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methanol(9.56 g, 40.0 mmol) and sodium borohydride (7.0 g, 200 mL) in carbondisulfide (100 mL) under a try N2 atmosphere over a period of 30 min.After an additional 3 hours, the reaction mixture was carefully quenchedand further diluted with aqueous ammonium chloride (250 mL). Aqueousmixture was extracted with ethyl ether (500 mL). The ethyl ether extractwas washed with water and brine. Silica gel (100 mL) was added. Solventswere removed and the silica adsorbate was flash chromatographed (eluent99:1 petroleum ether: ethyl acetate) to provide the title compound as anoil (3.75 g, 42%): NMR (CDCl3); δ7.74 (d, J=8 Hz, 1H), 7.67 (d, J=8, Hz,1H), 7.35-7.22 (m, 2H), 7.08 (d, J=1 Hz, 1H), 5.93 (s, 1H), 4.15 (s,2H), 2.17 (s, 3H), 1.90 (s, 3H); MS (EI): [M+], 242.

EXAMPLE 4

4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenyl methylether

Tin tetrachloride (7.6 mL, 65.2 mmol) was added dropwise to a -78° C.,stirred solution ofbenzo[b]thiophen-2-yl-(2,3-dimethyl-furan-5-yl)-methane (3.96 g, 16.3mmol) and anisoyl chloride (3.07 g, 17.93 mL) in carbon disulfide (100mL) under a try N2 atmosphere over a period of 30 min. After theaddition completed, the solution was allowed to warm to 0° C. After 9 h.the reaction mixture was carefully quenched with and further dilutedwith water (350 mL). Aqueous mixture was extracted with ethyl ether. Theethyl ether extracts were washed with water, 10% aqueous sodiumbicarbonate and water and dried with brine. Silica gel (90 mL) wasadded. Solvents were removed and the silica adsorbate was flashchromatographed (eluent 99:1 petroleum ether:ethyl acetate) to providethe title compound as a light yellow solid (1.1 g, 25%): NMR (CDCl3);δ7.81 (s, 1H), 7.76 (d, J=8, Hz, 1H), 7.36-7.24 (m, 3H), 7.11-7.00 (m,3H), 6.85 (d, J=8 Hz, 1H), 3.96 (s, 3H), 2.37 (s, 3H), 1.55 (s, 3H); MS(EI): [M+], 358.

EXAMPLE 5

4-(2,3-Dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenol

Boron tribromide (1.0 M solution in methylene chloride, 14.7 mL, 14.7mmol) was added dropwise to a -78° C., stirred solution of4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenyl methylether (1.05 g, 2.9 mmol) in methylene chloride (42 mL) under a try N2atmosphere. After 40 min., the solution was allowed to warm to ambienttemperature. After 2.5 h. the reaction mixture was carefully quenchedwith 10% aqueous sodium bisulfide and further diluted with water (150mL). Aqueous mixture was extracted with methylene chloride (300 mL). Themethylene chloride extract was washed with water and dried with brine.Silica gel (25 mL) was added. Solvents were removed and the silicaadsorbate was flash chromatographed (eluent 85:15 petroleum ether:ethylacetate) to provide the methyl ester as a brown solid (0.951 g, 94%).:mp 174-175° C.: NMR (CDCl3): δ7.81 (s, 1H), 7.76 (d, J=8, Hz, 1H),7.31-7.27(m, 3H), 7.08-7.00 (m, 3H), 6.87 (d, J=8 Hz, 1H), 5.00 (s, 1H),2.37 (s, 3H), 1.58 (s, 3H); MS (EI): [M+], 344.

EXAMPLE 6

4-(2,3-Dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenol

Iodine (0.701 g, 2.76 mmol) was added portionwise to a stirred, 0° C.solution of4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenol (0.336 g,1.06 mmol), sodium hydroxide (97%, 0.087 g, 2.12 mmol) in methanol (17mL) over a period of 30 min. and the mixture was stirred at 0° C. for2.5 h. and at ambient temperature for 15 h. The reaction mixture wasquenched with 10% aqueous hydrochloride to pH 1 and diluted with water.Aqueous mixture was extracted with ethyl acetate (100 mL). The ethylacetate was washed with 5% sodium bisulfite (50 mL) and water and driedwith brine. Silica gel (8 mL) was added. Solvent was removed and theadsorbate was flash chromatographed (eluent 75:25 petroleumether:methylene chloride) to provide the title compound as a white solid(0.34 g, 54%): NMR (CDCl3); δ7.83 (s, 1H), 7.81 (s, 2H), 7.80 (d, J=8,Hz, 1H), 7.33 (dd, J=8, 7, Hz, 1H), 7.15 (dd, J=8, 7, Hz, 1H), 6.98 (d,J=8 Hz, 1H), 5.99 (s, 1H), 2.37 (s, 3H), 1.61 (s, 3H); MS (EI): [M+],596.

EXAMPLE 7

(S)-2-Hydroxy-3-phenylpropionic acid, methyl ester

A solution of commercially available (S)-2-hydroxy-3-phenylpropionicacid (5.0 g, 30.1 mmol) and p-toluenesulfonic acid hydrate (1 g) inmethanol (125 mL) was refluxed with removal of water using 3A molecularsieves for 17 h. The solution was concentrated and dissolved in ether.The ether solution was washed with saturated sodium bicarbonate, brineand concentrated to provide the title compound as a white solid (5.32 g,98%): NMR (CDCl3); δ7.36-7.20 (m, 5H), 4.47 (ddd, J=5, 6, 7 Hz, 1H),3.78 (s, 3H), 3.14 (dd, J=5, 14 Hz, 1H), 2.97 (dd, J=7, 14 Hz), 2.69 (d,J=6 Hz, 1H).

EXAMPLE 8

(R)-2-[4-(2,3-Dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-propionicacid

Diethylazodicarboxylate (0.075 mL, 0.48 mmol) was added dropwise to astirred, ambient temperature solution of4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenol(0.19 g, 0.32 mmol), methyl(-s)-(-)lactate (98%, 0.050 g, 0.48 mmol) andtriphenylphosphine (0.125 g, 0.48 mmol) in benzene (1.6 mL) under a drynitrogen atmosphere. The solution was heated in an 80° C. oil bath for3.0 h. Upon cooling to room temperature, the reaction mixture wasdiluted with dichloromethane and silica gel (3 mL) was added. Solventswere removed and the silica adsorbate was flash chromatographed (eluent9:1 petroleum ether:ethyl acetate) to provide the methyl ester as awhite solid (0.113 g, 52%): Aqueous potassium hydroxide (1.0 N, 0.36 mL,0.36 mmol) was added to a stirred solution of this methyl ester (0.110g, 0.161 mmol) in dioxane (1.0 mL) at ambient temperature. After 32 h,the reaction mixture was quenched with 10% aqueous hydrochloride to pH 1and further diluted with water (40 mL). Aqueous mixture was extractedwith ethyl ether (50 mL). The ethyl ether extract was washed with water,dried with brine and anhydrous MgSO4, and concentrated to provide thetitle compound as an off-white solid (0.104 g, 96%): mp 218-219° C.: NMR(CDCl3): δ7.97 (s, 2H), 7.85 (s, 1H), 7.81 (d, J=8, Hz, 1H), 7.34 (ddd,J=8, 7, 1 Hz, 1H), 7.12 (ddd, J=8, 7, 1 Hz, 1H), 6.87 (d, J=8 Hz, 1H),5.46 (q, J=7 Hz, 1H, CH), 2.38 (s, 3H), 1.77 (d, J=7 Hz, 3H), 1.61 (s,3H); MS (+FAB): [M+], 667.8, [M+H]+, 668.9; Anal. Calc. for C25H18I2O4S:C, 44.93, H, 2.72, N, 0.00. Found: C, 44.77, H, 2.63, N, 0.20.

EXAMPLE 9

(R)-2-[4-(2,3-Dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-3-phenyl-propionicacid

Prepared from4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoland (S)-2-hydroxy-3-phenylpropionic acid, methyl ester according to theprocedure in Example 8 to provide the title compound as a white solid:mp 215-217: NMR (DMSO-d6): δ8.17 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.85 (d,J=4 Hz, 2H), 7.39-7.30 (m, 5H), 7.22 (dd, J=7 Hz, 1H), 7.16 (dd, J=7, 1Hz, 1H), 6.87 (d, J=8 Hz, 1H), 5.41 (s, 1H), 3.43 (dd, J=6, 1 Hz, 2H),2.36 (s, 3H), 1.56 (s, 3H); MS (+FAB): [M+H]+, 745; Anal. Calc. forC31H22I2O4S: C, 50.02, H, 2.98, N, 0.00. Found: C,47.59, H, 2.98, N,0.13.

What is claimed is:
 1. A compound of formula I having the structure##STR8## wherein B and D are each, independently, hydrogen, halogen,--CN, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbonatoms;R¹ is hydrogen, alkyl of 1-6 carbon atoms, --CH(R²)W, --C(CH₃)₂CO₂ R³, --CH(⁴)CH₂ CO₂ R³, --COR³, or --PO₃ (R³)₂ ; R² is hydrogen,alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; W is--CO₂ R³, --CONH₂, --CONHOH, --CN, CONH(CH₂)₂ CN, or --PO₃ (R³)₂ ; R³ ishydrogen, alkyl of 1-6 carbon atoms, or aryl; R⁴ is hydrogen or alkyl of1-6 carbon atoms; aryl and the aryl portion of the arylalkyl group areeach, independently, phenyl or naphthyl, wherein the aryl moiety may beoptionally mono-, di-, or tri-substituted with a substituent selectedfrom the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbonatoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each ofthe alkyl groups is of 1-6 carbon atoms, nitro, cyano, --CO₂ H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms, or a pharmaceutically acceptable salt thereof.
 2. The compoundaccording to claim 1, wherein B and D are halogen.
 3. The compoundaccording to claim 2, wherein R¹ is hydrogen or --CH(R²)W.
 4. Thecompound according to claim 3, whereinR² is hydrogen, alkyl of 1-6carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; W is --CO₂ R³, orCONH₂, and R³ is hydrogen, or alkyl of 2-6 carbon atoms.
 5. The compoundaccording to claim 1, which is4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenyl methylether.
 6. The compound according to claim 1, which is4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-phenol or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 1, which is4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenolor a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 1, which is(R)-2-[4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-propionicacid or a pharmaceutically acceptable salt thereof.
 9. The compoundaccording to claim 1, which is(R)-2-[4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenoxy]-3-phenyl-propionicacid or a pharmaceutically acceptable salt thereof.
 10. A method oftreating metabolic disorders mediated by insulin resistance orhyperglycemia in a mammal in need thereof which comprises administeringto said mammal, a compound of formula I having the structure ##STR9##wherein B and D are each, independently, hydrogen, halogen, --CN, alkylof 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;R¹ ishydrogen, alkyl of 1-6 carbon atoms, --CH(R²)W, --C(CH₃)₂ CO₂ R³,--CH(R⁴)CH₂ CO₂ R₃, --COR³, or --PO₃ (R³)₂ ; R² is hydrogen, alkyl of1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl; W is --CO₂ R³,--CONH₂, --CONHOH, --CN, CONH(CH₂)₂ CN, or --PO₃ (R³)₂ ; R³ is hydrogen,alkyl of 1-6 carbon atoms, or aryl; R⁴ is hydrogen or alkyl of 1-6carbon atoms; aryl and the aryl portion of the arylalkyl each,independently, phenyl or naphthyl, wherein the aryl moiety may beoptionally mono-, di-, or tri-substituted with a substituent selectedfrom the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6carbon atoms, trifluoromethyl, halogen, alkoxycarbonyl of 2-7 carbonatoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each ofthe alkyl groups is of 1-6 carbon atoms nitro, cyano, --CO₂ H,alkylcarbonyloxy of 2-7 carbon atoms, and alkylcarbonyl of 2-7 carbonatoms, or a pharmaceutically acceptable salt thereof.
 11. A method oftreating or inhibiting type II diabetes in a mammal in need thereofwhich comprises administering to said mammal, a compound of formula Ihaving the structure ##STR10## wherein B and D are each, independently,hydrogen, halogen, --CN, alkyl of 1-6 carbon atoms, aryl, or aralkyl of6-12 carbon atoms;R¹ is hydrogen, alkyl of 1-6 carbon atoms, --CH(R²)W,--C(CH₃)₂ CO₂ R³, --CH(⁴)CH₂ CO₂ R³, --COR³, or --PO₃ (R³)₂ ; R² ishydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, oraryl; W is --CO₂ R³, --CONH, --CONHOH, --CN, CONH(CH₂)₂ CN, or --PO₃(R³)₂ ; R³ is hydrogen, alkyl of 1-6 carbon atoms, or aryl; R⁴ ishydrogen or alkyl of 1-6 carbon atoms; aryl and the aryl portion of thearylalkyl group are each, independently, phenyl or naphthyl, wherein thearyl moiety may be optionally mono-, di-, or tri-substituted with asubstituent selected from the group consisting of alkyl of 1-6 carbonatoms, alkoxy of 1-6 carbon atoms, trifluoromethyl halogen,alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, anddialkylamino in which each of the alkyl groups is of 1-6 carbon atoms,nitro, cyano, --CO₂ H, alkylcarbonyloxy of 2-7 carbon atoms, andalkylcarbonyl of 2-7 carbon atoms, or a pharmaceutically acceptable saltthereof.
 12. A method of modulating glucose levels in a mammal in needthereof which comprises administering to said mammal, a compound offormula I having the structure ##STR11## wherein B and D are each,independently, hydrogen, halogen, --CN, alkyl of 1-6 carbon atoms, aryl,or aralkyl of 6-12 carbon atoms;R¹ is hydrogen, alkyl of 1-6 carbonatoms, --CH(R²)W, --C(CH₃)₂ CO₂ R³, --CH(⁴)CH₂ CO₂ R³, --COR³, or --PO₃(R³)₂ ; R² is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12carbon atoms, or aryl; W is --CO₂ R³, --CONH₂, --CONHOH, --CN,CONH(CH₂)₂ CN, or --PO₃ (R³)₂ ; R³ is hydrogen, alkyl of 1-6 carbonatoms, or aryl; R⁴ is hydrogen or alkyl of 1-6 carbon atoms; aryl andthe aryl portion of the arylalkyl group are each, independently, phenylor naphthyl, wherein the aryl moiety may be optionally mono-, di-, ortri-substituted with a substituent selected from the group consisting ofalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl,halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbonatoms, and dialkylamino in which each of the alkyl groups is of 1-6carbon atoms, nitro, cyano, --CO₂ H, alkylcarbonyloxy of 2-7 carbonatoms, and alkylcarbonyl of 2-7 carbon atoms, or a pharmaceuticallyacceptable salt thereof.
 13. A pharmaceutical composition whichcomprises a compound of formula I having the structure ##STR12## whereinB and D are each, independently, hydrogen, halogen, --CN, alkyl of 1-6carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;R¹ is hydrogen,alkyl of 1-6 carbon atoms, --CH(R²)W, --C(CH₃)₂ CO₂ R³, --CH(R⁴)CH₂ CO₂R³, --COR³, or --PO₃ (R³)₂ ; R² is hydrogen, alkyl of 1-6 carbon atoms,aralkyl of 6-12 carbon atoms, or aryl; W is --CO₂ R³, --CONH₂, --CONHOH,--CN, CONH(CH₂)₂ CN, or --PO₃ (R³)₂ ; R³ is hydrogen, alkyl of 1-6carbon atoms, or aryl; R⁴ is hydrogen or alkyl of 1-6 carbon atoms; aryland the aryl portion of the group are each, independently, phenyl ornaphthyl, wherein the aryl moiety may be optionally mono-, di-, ortri-substituted with a substituent selected from the group consisting ofalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl,halogen, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbonatoms, and dialkylamino in which each of the alkyl groups is of 1-6carbon atoms, nitro, cyano, --CO₂ H, alkylcarbonyloxy of 2-7 carbonatoms, and alkylcarbonyl of 2-7 carbon atoms, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutical carrier.